Delivery of stimulants through an inhalation route

ABSTRACT

The present invention relates to the delivery of stimulants through an inhalation route. Specifically, it relates to aerosols containing stimulants that are used in inhalation therapy. In a method aspect of the present invention, a stimulant is delivered to a patient through an inhalation route. The method comprises: a) heating a coating of a stimulant, on a solid support, to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles having less than 5% stimulant degradation products. In a kit aspect of the present invention, a kit for delivering a stimulant through an inhalation route is provided which comprises: a) a coating of a stimulant drug and b) a device for dispensing said coating a stimulant as a condensation aerosol.

This application is a continuation of U.S. patent application Ser. No.10/816,492 issued as U.S. Pat. No. 7,008,616, which is a continuation ofU.S. patent application Ser. No. 10/150,268 issued as U.S. Pat. No.6,780,399, entitled “Delivery of Stimulants Through an InhalationRoute,” filed May 15, 2002, Rabinowitz and Zaffaroni, which claimspriority to U.S. provisional application Ser. No. 60/294,203 entitled“Thermal Vapor Delivery of Drugs,” filed May 24, 2001, Rabinowitz andZaffaroni, the entire disclosure of which is hereby incorporated byreference. This application further claims priority to U.S. provisionalapplication Ser. No. 60/317,479 entitled “Aerosol Drug Delivery,” filedSep. 5, 2001, Rabinowitz and Zaffaroni, the entire disclosure of whichis hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to the delivery of stimulants through aninhalation route. Specifically, it relates to aerosols containingephedrine or fenfluramine that are used in inhalation therapy.

BACKGROUND OF THE INVENTION

There are a number of compositions currently marketed as stimulants. Thecompositions contain at least one active ingredient that provides forobserved therapeutic effects. Among the active ingredients given instimulant compositions are ephedrine and fenfluramine.

It is desirable to provide a new route of administration for ephedrineand fenfluramine that rapidly produces peak plasma concentrations of thecompounds. The provision of such a route is an object of the presentinvention.

SUMMARY OF THE INVENTION

The present invention relates to the delivery of stimulants through aninhalation route. Specifically, it relates to aerosols containingephedrine or fenfluramine that are used in inhalation therapy.

In a composition aspect of the present invention, the aerosol comprisesparticles comprising at least 5 percent by weight of ephedrine orfenfluramine. Preferably, the particles comprise at least 10 percent byweight of ephedrine or fenfluramine. More preferably, the particlescomprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent or 99.97 percent by weight of ephedrine orfenfluramine.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofephedrine or fenfluramine degradation products. Preferably, theparticles comprise less than 5 percent by weight of ephedrine orfenfluramine degradation products. More preferably, the particlescomprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight ofephedrine or fenfluramine degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, at least 50 percent by weight of the aerosol is amorphous inform, wherein crystalline forms make up less than 50 percent by weightof the total aerosol weight, regardless of the nature of individualparticles. Preferably, at least 75 percent by weight of the aerosol isamorphous in form. More preferably, at least 90 percent by weight of theaerosol is in amorphous form.

Typically, where the aerosol comprises ephedrine, the aerosol has aninhalable aerosol drug mass density of between 2 mg/L and 20 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 2 mg/L and 15 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 2 mg/L and 12.5 mg/L.

Typically, where the aerosol comprises fenfluramine, the aerosol has aninhalable aerosol drug mass density of between 4 mg/L and 30 mg/L.Preferably, the aerosol has an inhalable aerosol drug mass density ofbetween 4 mg/L and 25 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 4 mg/L and 22.5 mg/L.

Typically, the aerosol has an inhalable aerosol particle density greaterthan 10⁶ particles/mL. Preferably, the aerosol has an inhalable aerosolparticle density greater than 10⁷ particles/mL or 10⁸ particles/mL.

Typically, the aerosol particles have a mass median aerodynamic diameterof less than 5 microns. Preferably, the particles have a mass medianaerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.1.

Typically, the aerosol is formed by heating a composition containingephedrine or fenfluramine to form a vapor and subsequently allowing thevapor to condense into an aerosol.

In a method aspect of the present invention, either ephedrine orfenfluramine is delivered to a mammal through an inhalation route. Themethod comprises: a) heating a composition, wherein the compositioncomprises at least 5 percent by weight of ephedrine or fenfluramine, toform a vapor; and, b) allowing the vapor to cool, thereby forming acondensation aerosol comprising particles, which is inhaled by themammal. Preferably, the composition that is heated comprises at least 10percent by weight of ephedrine or fenfluramine. More preferably, thecomposition comprises at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of ephedrine or fenfluramine.

Typically, the particles comprise at least 5 percent by weight ofephedrine or fenfluramine. Preferably, the particles comprise at least10 percent by weight of ephedrine or fenfluramine. More preferably, theparticles comprise at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of ephedrine or fenfluramine.

Typically, the aerosol has a mass of at least 10 μg. Preferably, theaerosol has a mass of at least 100 μg. More preferably, the aerosol hasa mass of at least 200 μg.

Typically, the particles comprise less than 10 percent by weight ofephedrine or fenfluramine degradation products. Preferably, theparticles comprise less than 5 percent by weight of ephedrine orfenfluramine degradation products. More preferably, the particlescomprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of ephedrine orfenfluramine degradation products.

Typically, the particles comprise less than 90 percent by weight ofwater. Preferably, the particles comprise less than 80 percent by weightof water. More preferably, the particles comprise less than 70 percent,60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent,or 5 percent by weight of water.

Typically, the particles of the delivered condensation aerosol have amass median aerodynamic diameter of less than 5 microns. Preferably, theparticles have a mass median aerodynamic diameter of less than 3microns. More preferably, the particles have a mass median aerodynamicdiameter of less than 2 or 1 micron(s).

Typically, the geometric standard deviation around the mass medianaerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.1.

Typically, where the aerosol comprises ephedrine, the delivered aerosolhas an inhalable aerosol drug mass density of between 2 mg/L and 20mg/L. Preferably, the aerosol has an inhalable aerosol drug mass densityof between 2 mg/L and 15 mg/L. More preferably, the aerosol has aninhalable aerosol drug mass density of between 2 mg/L and 12.5 mg/L.

Typically, where the aerosol comprises fenfluramine, the deliveredaerosol has an inhalable aerosol drug mass density of between 4 mg/L and30 mg/L. Preferably, the aerosol has an inhalable aerosol drug massdensity of between 4 mg/L and 25 mg/L. More preferably, the aerosol hasan inhalable aerosol drug mass density of between 4 mg/L and 22.5 mg/L.

Typically, the delivered aerosol has an inhalable aerosol particledensity greater than 10⁶ particles/mL. Preferably, the aerosol has aninhalable aerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

Typically, the rate of inhalable aerosol particle formation of thedelivered condensation aerosol is greater than 10⁸ particles per second.Preferably, the aerosol is formed at a rate greater than 10⁹ inhalableparticles per second. More preferably, the aerosol is formed at a rategreater than 10¹⁰ inhalable particles per second.

Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

Typically, where the condensation aerosol comprises ephedrine, between 2mg and 20 mg of ephedrine are delivered to the mammal in a singleinspiration. Preferably, between 2 mg and 15 mg of ephedrine aredelivered to the mammal in a single inspiration. More preferably,between 2 mg and 12.5 mg of ephedrine are delivered in a singleinspiration.

Typically, where the condensation aerosol comprises fenfluramine,between 4 mg and 30 mg of fenfluramine are delivered to the mammal in asingle inspiration. Preferably, between 4 mg and 25 mg of fenfluramineare delivered to the mammal in a single inspiration. More preferably,between 4 mg and 22.5 mg of fenfluramine are delivered to the mammal ina single inspiration.

Typically, the delivered condensation aerosol results in a peak plasmaconcentration of ephedrine or fenfluramine in the mammal in less than 1h. Preferably, the peak plasma concentration is reached in less than 0.5h. More preferably, the peak plasma concentration is reached in lessthan 0.2, 0.1, 0.05, 0.02 or 0.01 h.

In a kit aspect of the present invention, a kit for delivering ephedrineor fenfluramine through an inhalation route to a mammal is providedwhich comprises: a) a composition comprising at least 5 percent byweight of ephedrine or fenfluramine; and, b) a device that forms anephedrine or fenfluramine aerosol from the composition, for inhalationby the mammal. Preferably, the composition comprises at least 20percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent,99.9 percent or 99.97 percent by weight of ephedrine or fenfluramine.

Typically, the device contained in the kit comprises: a) an element forheating the ephedrine or fenfluramine composition to form a vapor; b) anelement allowing the vapor to cool to form an aerosol; and, c) anelement permitting the mammal to inhale the aerosol.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 shows a cross-sectional view of a device used to deliverephedrine or fenfluramine aerosols to a mammal through an inhalationroute.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“Aerodynamic diameter” of a given particle refers to the diameter of aspherical droplet with a density of 1 g/mL (the density of water) thathas the same settling velocity as the given particle.

“Aerosol” refers to a suspension of solid or liquid particles in a gas.

“Aerosol drug mass density” refers to the mass of ephedrine orfenfluramine per unit volume of aerosol.

“Aerosol mass density” refers to the mass of particulate matter per unitvolume of aerosol.

“Aerosol particle density” refers to the number of particles per unitvolume of aerosol.

“Amorphous particle” refers to a particle that does not contain morethan 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent of a crystalline form.

“Condensation aerosol” refers to an aerosol formed by vaporization of asubstance followed by condensation of the substance into an aerosol.

“Ephedrine” refers to 2-methylamino-1-phenyl-1-propanol.

“Ephedrine degradation product” refers to a compound resulting from achemical modification of ephedrine. The modification, for example, canbe the result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Fenfluramine” refers to2-ethylamino-1-(3-trifluoromethylphenyl)propane.

“Fenfluramine degradation product” refers to a compound resulting from achemical modification of fenfluramine. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis.

“Inhalable aerosol drug mass density” refers to the aerosol drug massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

“Inhalable aerosol mass density” refers to the aerosol mass densityproduced by an inhalation device and delivered into a typical patienttidal volume.

“Inhalable aerosol particle density” refers to the aerosol particledensity of particles of size between 100 nm and 5 microns produced by aninhalation device and delivered into a typical patient tidal volume.

“Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to theaerodynamic diameter for which half the particulate mass of the aerosolis contributed by particles with an aerodynamic diameter larger than theMMAD and half by particles with an aerodynamic diameter smaller than theMMAD.

“Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

“Rate of inhalable aerosol particle formation” refers to the number ofparticles of size between 100 nm and 5 microns produced by an inhalationdevice per unit time.

“Rate of drug aerosol formation” refers to the mass of aerosolizedephedrine or fenfluramine produced by an inhalation device per unittime.

“Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

“Typical patient tidal volume” refers to 1 L for an adult patient and 15mL/kg for a pediatric patient.

“Vapor” refers to a gas, and “vapor phase” refers to a gas phase. Theterm “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

Formation of Ephedrine or Fenfluramine Containing Aerosols

Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising ephedrine or fenfluramine to form a vapor, followed bycooling of the vapor such that it condenses to provide an ephedrine orfenfluramine comprising aerosol (condensation aerosol). The compositionis heated in one of four forms: as pure active compound (i.e., pureephedrine or fenfluramine); as a mixture of active compound and apharmaceutically acceptable excipient; as a salt form of the pure activecompound; and, as a mixture of active compound salt form and apharmaceutically acceptable excipient.

Salt forms of ephedrine or fenfluramine are either commerciallyavailable or are obtained from the corresponding free base using wellknown methods in the art. A variety of pharmaceutically acceptable saltsare suitable for aerosolization. Such salts include, without limitation,the following: hydrochloric acid, hydrobromic acid, acetic acid, maleicacid, formic acid, and fumaric acid salts.

Pharmaceutically acceptable excipients may be volatile or nonvolatile.Volatile excipients, when heated, are concurrently volatilized,aerosolized and inhaled with ephedrine or fenfluramine. Classes of suchexcipients are known in the art and include, without limitation,gaseous, supercritical fluid, liquid and solid solvents. The followingis a list of exemplary carriers within the classes: water; terpenes,such as menthol; alcohols, such as ethanol, propylene glycol, glyceroland other similar alcohols; dimethylformamide; dimethylacetamide; wax;supercritical carbon dioxide; dry ice; and mixtures thereof.

Solid supports on which the composition is heated are of a variety ofshapes. Examples of such shapes include, without limitation, cylindersof less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness andvirtually any shape permeated by small (e.g., less than 1.0 mm-sized)pores. Preferably, solid supports provide a large surface to volumeratio (e.g., greater than 100 per meter) and a large surface to massratio (e.g., greater than 1 cm² per gram).

A solid support of one shape can also be transformed into another shapewith different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yams and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

Where aluminum is used as a solid support, aluminum foil is a suitablematerial. Examples of silica, alumina and silicon based materialsinclude amphorous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (analumina of defined surface area greater than 2 m²/g from Aldrich, St.Louis, Mo.) and a silicon wafer as used in the semiconductor industry.Carbon yams and felts are available from American Kynol, Inc., New York,N.Y. Chromatography resins such as octadecycl silane chemically bondedto porous silica are exemplary coated variants of silica.

The heating of the ephedrine or fenfluramine compositions is performedusing any suitable method. Examples of methods by which heat can begenerated include the following: passage of current through anelectrical resistance element; absorption of electromagnetic radiation,such as microwave or laser light; and, exothermic chemical reactions,such as exothermic salvation, hydration of pyrophoric materials andoxidation of combustible materials.

Delivery of Ephedrine or Fenfluramine Containing Aerosols

Ephedrine or fenfluramine containing aerosols of the present inventionare delivered to a mammal using an inhalation device. Where the aerosolis a condensation aerosol, the device has at least three elements: anelement for heating an ephedrine or fenfluramine containing compositionto form a vapor; an element allowing the vapor to cool, therebyproviding a condensation aerosol; and, an element permitting the mammalto inhale the aerosol. Various suitable heating methods are describedabove. The element that allows cooling is, in it simplest form, an inertpassageway linking the heating means to the inhalation means. Theelement permitting inhalation is an aerosol exit portal that forms aconnection between the cooling element and the mammal's respiratorysystem.

One device used to deliver the ephedrine or fenfluramine containingaerosol is described in reference to FIG. 1. Delivery device 100 has aproximal end 102 and a distal end 104, a heating module 106, a powersource 108, and a mouthpiece 110. An ephedrine or fenfluraminecomposition is deposited on a surface 112 of heating module 106. Uponactivation of a user activated switch 114, power source 108 initiatesheating of heating module 106 (e.g, through ignition of combustible fuelor passage of current through a resistive heating element). Theephedrine or fenfluramine composition volatilizes due to the heating ofheating module 106 and condenses to form a condensation aerosol prior toreaching the mouthpiece 110 at the proximal end of the device 102. Airflow traveling from the device distal end 104 to the mouthpiece 110carries the condensation aerosol to the mouthpiece 110, where it isinhaled by the mammal.

Devices, if desired, contain a variety of components to facilitate thedelivery of ephedrine or fenfluramine containing aerosols. For instance,the device may include any component known in the art to control thetiming of drug aerosolization relative to inhalation (e.g.,breath-actuation), to provide feedback to patients on the rate and/orvolume of inhalation, to prevent excessive use (i.e., “lock-out”feature), to prevent use by unauthorized individuals, and/or to recorddosing histories.

Dosage of Ephedrine or Fenfluramine Containing Aerosols

Ephedrine and fenfluramine are given at strengths of 10 mg and 20 mgrespectively for appetite suppression. As aerosols, 2 mg to 20 mg ofephendrine, and 4 mg to 30 mg of fenfluramine are generally provided perinspiration for the same indication. A typical dosage of an ephedrine orfenfluramine aerosol is either administered as a single inhalation or asa series of inhalations taken within an hour or less (dosage equals sumof inhaled amounts). Where the drug is administered as a series ofinhalations, a different amount may be delivered in each inhalation. Thedosage amount of ephedrine or fenfluramine in aerosol form is generallyno greater than twice the standard dose of the drug given orally.

One can determine the appropriate dose of ephedrine or fenfluraminecontaining aerosols to treat a particular condition using methods suchas animal experiments and a dose-finding (Phase I/II) clinical trial.One animal experiment involves measuring plasma concentrations of drugin an animal after its exposure to the aerosol. Mammals such as dogs orprimates are typically used in such studies, since their respiratorysystems are similar to that of a human. Initial dose levels for testingin humans is generally less than or equal to the dose in the mammalmodel that resulted in plasma drug levels associated with a therapeuticeffect in humans. Dose escalation in humans is then performed, untileither an optimal therapeutic response is obtained or a dose-limitingtoxicity is encountered.

Analysis of Ephedrine or Fenfluramine Containing Aerosols

Purity of an ephedrine or fenfluramine containing aerosol is determinedusing a number of methods, examples of which are described in Sekine etal., Journal of Forensic Science 32:1271-1280 (1987) and Martin et al.,Journal of Analytic Toxicology 13:158-162 (1989). One method involvesforming the aerosol in a device through which a gas flow (e.g., airflow) is maintained, generally at a rate between 0.4 and 60 L/min. Thegas flow carries the aerosol into one or more traps. After isolationfrom the trap, the aerosol is subjected to an analytical technique, suchas gas or liquid chromatography, that permits a determination ofcomposition purity.

A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

The gas or liquid chromatograph discussed above contains a detectionsystem (i.e., detector). Such detection systems are well known in theart and include, for example, flame ionization, photon absorption andmass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure of ephedrineor fenfluramine degradation products.

Particle size distribution of an ephedrine or fenfluramine containingaerosol is determined using any suitable method in the art (e.g.,cascade impaction). An Andersen Eight Stage Non-viable Cascade Impactor(Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mockthroat (USP throat, Andersen Instruments, Smyrna, Ga.) is one systemused for cascade impaction studies.

Inhalable aerosol mass density is determined, for example, by deliveringa drug-containing aerosol into a confined chamber via an inhalationdevice and measuring the mass collected in the chamber. Typically, theaerosol is drawn into the chamber by having a pressure gradient betweenthe device and the chamber, wherein the chamber is at lower pressurethan the device. The volume of the chamber should approximate the tidalvolume of an inhaling patient.

Inhalable aerosol drug mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size is determined bymeasuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*φ/6, whereD is a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, φ is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

Rate of inhalable aerosol particle formation is determined, for example,by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

Rate of aerosol formation is determined, for example, by deliveringaerosol phase drug into a confined chamber via an inhalation device. Thedelivery is for a set period of time (e.g., 3 s), and the mass ofparticulate matter collected is determined by weighing the confinedchamber before and after the delivery of the particulate matter. Therate of aerosol formation is equal to the increase in mass in thechamber divided by the duration of the collection time. Alternatively,where a change in mass of the delivery device or component thereof canonly occur through release of the aerosol phase particulate matter, themass of particulate matter may be equated with the mass lost from thedevice or component during the delivery of the aerosol. In this case,the rate of aerosol formation is equal to the decrease in mass of thedevice or component during the delivery event divided by the duration ofthe delivery event.

Rate of drug aerosol formation is determined, for example, by deliveringan ephedrine or fenfluramine containing aerosol into a confined chambervia an inhalation device over a set period of time (e.g., 3 s). Wherethe aerosol is pure ephedrine or fenfluramine, the amount of drugcollected in the chamber is measured as described above. The rate ofdrug aerosol formation is equal to the amount of ephedrine orfenfluramine collected in the chamber divided by the duration of thecollection time. Where the ephedrine or fenfluramine containing aerosolcomprises a pharmaceutically acceptable excipient, multiplying the rateof aerosol formation by the percentage of ephedrine or fenfluramine inthe aerosol provides the rate of drug aerosol formation.

Utility of Ephedrine or Fenfluramine Containing Aerosols

The ephedrine or fenfluramine containing aerosols of the presentinvention are typically used for appetite suppression, for increasingone's energy level, or for a positive inotropic effect.

The following examples are meant to illustrate, rather than limit, thepresent invention.

Ephedrine and fenfluramine hydrochloride are commercially available fromSigma (www.sigma-aldrich.com).

EXAMPLE 1 General Procedure for Obtaining Free Base of a Compound Salt

Approximately 1 g of salt (e.g., mono hydrochloride) is dissolved indeionized water (˜30 mL). Three equivalents of sodium hydroxide (1 NNaOH_(aq)) is added dropwise to the solution, and the pH is checked toensure it is basic. The aqueous solution is extracted four times withdichloromethane (˜50 mL), and the extracts are combined, dried (Na₂SO₄)and filtered. The filtered organic solution is concentrated using arotary evaporator to provide the desired free base. If necessary,purification of the free base is performed using standard methods suchas chromatography or recrystallization.

EXAMPLE 2 General Procedure for Volatilizing Compounds from Halogen Bulb

A solution of drug in approximately 120 μL dichloromethane is coated ona 3.5 cm×7.5 cm piece of aluminum foil (precleaned with acetone). Thedichloromethane is allowed to evaporate. The coated foil is wrappedaround a 300 watt halogen tube (Feit Electric Company, Pico Rivera,Calif.), which is inserted into a glass tube sealed at one end with arubber stopper. Running 60 V of alternating current (driven by linepower controlled by a variac) through the bulb for 6 s or 90 V for 3.5 saffords thermal vapor (including aerosol), which is collected on theglass tube walls. Reverse-phase HPLC analysis with detection byabsorption of 225 nm light is used to determine the purity of theaerosol. (When desired, the system is flushed through with argon priorto volatilization.)

Ephedrine aerosol (7.26 mg) was obtained in approximately 99% purityusing this procedure, while fenfluramine aerosol (˜10 mg) was obtainedin approximately 100% purity.

1. A composition for delivery of ephedrine consisting of a condensationaerosol a. formed by volatilizing a coating of ephedrine on a solidsupport, having the surface texture of a metal foil, to a temperaturesufficient to produce a heated vapor of ephedrine and condensing theheated vapor of ephedrine to form condensation aerosol particles, b.wherein said condensation aerosol particles are characterized by lessthan 5% ephedrine degradation products, and c. the condensation aerosolhas an MMAD of less than 3 microns.
 2. The composition according toclaim 1, wherein the aerosol particles are formed at a rate of at least10⁹ particles per second.
 3. The composition according to claim 2,wherein the aerosol particles are formed at a rate of at least 10¹⁰particles per second.
 4. A composition for delivery of fenfluramineconsisting of a condensation aerosol a. formed by volatilizing a coatingof fenfluramine on a solid support, having the surface texture of ametal foil, to a temperature sufficient to produce a heated vapor offenfluramine and condensing the heated vapor of fenfluramine to formcondensation aerosol particles, b. wherein said condensation aerosolparticles are characterized by less than 5% fenfluramine degradationproducts, and c. the condensation aerosol has an MMAD of less than 3microns.
 5. The composition according to claim 4, wherein the aerosolparticles are formed at a rate of at least 10⁹ particles per second. 6.The composition according to claim 5, wherein the aerosol particles areformed at a rate of at least 10¹⁰ particles per second.
 7. A method ofproducing ephedrine in an aerosol form comprising: a. heating a coatingof ephedrine on a solid support, having the surface texture of a metalfoil, to a temperature sufficient to volatilize the ephedrine to form aheated vapor of the ephedrine, and b. during said heating, passing airthrough the heated vapor to produce aerosol particles of the ephedrinecomprising less than 5% ephedrine degradation products, and an aerosolhaving an MMAD of less than 3 microns.
 8. The method according to claim7, wherein the aerosol particles are formed at a rate of greater than10⁹ particles per second.
 9. The method according to claim 8, whereinthe aerosol particles are formed at a rate of greater than 10¹⁰particles per second
 10. A method of producing fenfluramine in anaerosol form comprising: a. heating a coating of fenfluramine on a solidsupport, having the surface texture of a metal foil, to a temperaturesufficient to volatilize the fenfluramine to form a heated vapor of thefenfluramine, and b. during said heating, passing air through the heatedvapor to produce aerosol particles of the fenfluramine comprising lessthan 5% fenfluramine degradation products, and an aerosol having an MMADof less than 3 microns.
 11. The method according to claim 10, whereinthe aerosol particles are formed at a rate of greater than 10⁹ particlesper second.
 12. The method according to claim 11, wherein the aerosolparticles are formed at a rate of greater than 10¹⁰ particles persecond.